366-373 watson

Management Issues of Neuropathic Trigeminal Pain
from a Medical Perspective

The purpose of this article is to review the pharmacological treat- ment of neuropathic trigeminal pain by means of a systematic review. A number of randomized controlled trials and important historical and uncontrolled studies in trigeminal neuralgia and postherpetic neuralgia were identified. Trigeminal neuralgia is aunique neuropathic pain disorder with a specific therapy. It does not respond to the usual drugs used for other neuropathic pains. The drug therapy of trigeminal postherpetic neuralgia is similar to that of other neuropathic trigeminal pain conditions. Key words: trigeminal neuralgia, neuropathic trigeminal pain,
“ Nous avons … l’essayer ( a diphenyl-hydantoine) dans… la névralgie épileptiforme de Trousseau. ; ce terme lui-même indique assez notre hypothèse de depart.” With the above logic (that trigeminal neuralgia resembles epilepsy with its paroxysms of pain, as described byTrousseau2) Bergouignan1 studied phenytoin and took the initial steps which led to the later 1960s reports by Blom ofcarbamazepine.3,4 Carbamazepine has been the most effectivetreatment for trigeminal neuralgia (TN). This article will outlineand contrast the pharmacotherapy of TN (tic douloureux) andpostherpetic neuralgia (PHN) in particular.
Trigeminal neuralgia is a condition unique to the trigeminal sys- tem and has its own specific therapy, consisting of both medicaland surgical components, which does not apply to most other headand orofacial pain conditions (except for glossopharyngeal neural-gia). Aside from some randomized controlled trials (RCTs) in TN,there is little scientific evidence bearing on management for anyother chronic neuropathic trigeminal pain condition, except forPHN; however, the evidence regarding PHN is lumped with non-trigeminal PHN. There is some data that the facial form of PHN ismore intractable. The drug therapy of PHN is more akin to thetreatment of other neuropathic facial pains such as anesthesiadolorosa, causalgia, and neuropathic pain below the neck. Theauthor will argue that this data (from PHN) can be extrapolated toneuropathic facial pain conditions other than TN. In order toreview and assess the literature on this subject, a systematic review COPYRIGHT 2004 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
NNT Data in Some Neuropathic Pain Conditions (Excludes Trigeminal Caution should be used in interpreting these figures as they involve studies of differing experimental designs, including selec-tion (inclusion criteria), numbers of patients, and data analyses. Because of differing selection in RCTs, NNT data may not begeneralizable to clinical practice.
was carried out using the terms “trigeminal neural- gia,” “postherpetic neuralgia,” and “treatment” to search Medline, Embase, Cinahl, PubMed, and the Cochrane Library. RCTs and important historicaland uncontrolled data were sought. Number- needed-to-treat (NNT) figures were sought from reviews and single articles in order to give to thereader an idea of the clinical meaningfulness of theresults of RCTs (Tables 1 and 2). NNT expresses use of phenytoin in this condition very soon after the number of patients in an RCT required to be the drug was first approved for use in epilepsy. In treated in order to obtain 50% or greater improve- the early 1960s, Blom reported that carbamazepine was more effective than phenytoin in preventing the (NNH) figures are calculated in the same way, but represent the patients in a clinical trial suffering Carbamazepine. A number of RCTs of carba- minor or major harm. These data need to be inter- mazepine followed the reports of Blom.15,16,19–21 A preted with some caution, taking into consideration systematic review5 considered 3 trials of carba- the differing methodologies, data analyses, and mazepine eligible for inclusion.15,19,21 One crossover numbers of patients, and as well as the selection study reported at least a very good response in 19 of (inclusion criteria) involved in these studies.
20 patients with up to 1,000 mg per day (versus noresponse with placebo). A second crossover designfound 15 of 20 (75%) with at least a good response (versus 6% with placebo). A third trial reported amean fall in pain of 58% with carbamazepine (ver- sus 26% with placebo).21 According to the system-atic review of McQuay et al,14 the NNT with carba- In the 1850s, Trousseau2 thought that painful mazepine for effectiveness versus placebo was 2.6 attacks of TN resembled epilepsy. Based on this (Table 2). The NNH for minor side effects was 3.4, idea, in 1942 Bergouignan1 described the successful and for drug-related withdrawal the NNH was 24.
Brief, lancinating pain that may be triggered by nonpainful stimuli and/or steady, burning pain, skin sensitivity, or sensory loss Try desipramine, amitriptyline, maprotiline hydromorphone, acid, mexiletine,selective inhibitors, topical agents (eg,capsaicin, acetylsalicylic acid, lidocaine) Two to 3 months constitutes a reasonable trial of medication for neuropathic pain.
*Stool softeners and laxatives can be used to treat or prevent constipation; saliva substi-tutes can be used to treat or prevent or dry mouth.
†Stool softeners and laxatives can be used to treat or prevent constipation; antiemeticscan be used to treat or prevent nausea. McQuay et al went on to discuss 3 RCTs using Other Drugs. Phenytoin was the first drug to be other agents, with carbamazepine as the control.
reported effective in TN. Uncontrolled data sug- Carbamazepine was found to be more effective than gest the utility of the benzodiazepine clonazepam tizanidine22 (an antispasticity drug) and no more or and the anticonvulsant valproate. Other drugs that less effective than tocainide23 (an antiarrhythmic).
Pimozide (an antipsychotic) was found to be supe- gabapentin and oxcarbazepine. The latter is rior to carbamazepine.24 Unfortunately, tocainide related to carbamazepine and is thought to have has been found to have serious hematologic side fewer adverse effects; it lacks enzyme induction effects, including death, and frequent adverse reac- and therefore should have fewer drug interactions.
tions have been found with pimozide. Sindrup and No NNT data are available for phenytoin, clon- Jensen6,25 concluded from several RCTs in TN that azepam, valproate, gabapentin, or oxcarbazepine Baclofen. Baclofen potentiates gamma-amino butyric acid (GABA) and is frequently used for spinal spasticity. It acts to facilitate segmental inhibitionand depresses excitatory transmission in the trigemi- The following recommendations are based on the nal brainstem subnucleus oralis in cats.26 Successful scientific evidence as well as the author’s clinical open label trials and an RCT using placebo18 have experience as a neurologist treating chronic pain demonstrated its efficacy. Baclofen has a synergistic action with carbamazepine. Baclofen is a racemic First-line Approach. The most successful treat- mixture, and the L isomer is 5 times as potent in ment of TN occurs with carbamazepine, which ini- TN.26 In a recent review, the NNT of baclofen was tially relieves the majority of sufferers when used appropriately. The dose of this drug is variable Lamotrigine. In an RCT, lamotrigine was effec- and can range from 200 mg to 2,000 mg per day tive when used as an add-on to carbamazepine or (bid or qid). A start-low-and-go-slow approach is phenytoin.17 An NNT of 2.1 was calculated for best. The author usually begins with a controlled- this drug when used in this fashion (Table 2).6 release preparation of 100 to 200 mg every 8 to 12 COPYRIGHT 2004 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
hours po, with prn rescue doses of the shorter-act- and the author finds it most useful as an add-on to ing preparation of 100 to 200 mg every 4 hours.
carbamazepine or to a combination of carba- Rescue medication may be timed to anticipate mazepine and baclofen. With add-on therapy, it is attacks that occur with eating, speaking, washing reasonable to use 100 mg in a single dose at bed- the face, or brushing the teeth. Dose escalation with time to start and to increase the dose slowly every the longer-acting preparation may then occur as 7 to 10 days, keeping to evening single dosing and needed. Blood levels can be used as a guide to com- using blood levels as a guide to compliance and pliance and dosage. If higher doses are accompa- dose increases. With this approach, one should be nied by lower blood levels, symptoms are uncon- mindful that there is no proven therapeutic range; trolled, and there are no significant side effects, the the end points are pain relief or intolerable side dose may be escalated. There is no therapeutic effects. Phenytoin has the advantage of being avail- range for TN, as has been suggested for epilepsy.
able intravenously for very severe pain that makes The author does not use an arbitrary ceiling for oral intake difficult. A loading dose of 15 mg/kg dosing but increases the dose until satisfactory may be used as for epilepsy and given slowly at a relief occurs or unacceptable side effects (eg, rate of 25 mg/min or less. The most common side drowsiness, ataxia, or nausea) are experienced. The effects of phenytoin are drowsiness, dizziness, most serious potential side effects of carbamazepine diplopia, and ataxia. These are dose related, but are aplastic anemia and hepatitis. Monitoring of may occur at low doses with combined therapy.
hematologic and hepatic parameters rarely results Other less common potential difficulties are gingi- in withdrawal of the drug but is prudent every 2 val hyperplasia, low folic acid levels, and idiosyn- weeks for the first 3 months of therapy and less fre- cratic reactions such as hepatitis, lupus, bone mar- quently thereafter. Dermatologic reactions, such as row depression, Stevens-Johnson syndrome, and Stevens-Johnson syndrome and lupus, may be seri- ous and require that therapy be stopped. Many Lamotrigine is a possibility as an add-on treat- patients will have good control of their pain with ment, but common side effects are a rash in 1 in carbamazepine, and after an appropriate period, it 1,000 and Stevens-Johnson syndrome in 3 in may be gradually reduced or withdrawn, as a 1,000. Close monitoring is required. If it is used as remission may occur. Future attacks may be more an add-on, the initial dose could be 25 mg/d for 2 readily treated with the knowledge about dosage weeks, then 25 mg bid for 2 weeks, with a maxi- that is gained from the first therapeutic experience.
Second-line Approach. Some patients are only Third-line Approaches. Other drugs of potential partially relieved by carbamazepine, and about use in refractory cases are the anticonvulsants 40% of patients experience side effects. Although clonazepam (3 to 8 mg/d), valproic acid (250 to the side effects often subside with time, about 10% 500 mg qid), gabapentin (300 mg/d to 1,200 mg require discontinuation of the drug. Long-term tid), and the antispasticity agent tizanidine or studies also indicate that only about 50% are oxcarbazepine. The author has seldom had good helped by carbamazepine after 6 to 16 years of success with these agents with patients who did treatment, perhaps because of the progression of not respond to carbamazepine, and refractory the disorder. It is the author’s practice to add patients may have to be referred for surgery, which baclofen if the response to carbamazepine is has a high success rate. Conventional analgesics, incomplete, or to use baclofen as a monotherapy if including opioids, do not satisfactorily relieve this carbamazepine has to be discontinued. The dose of pain. Interestingly, amitriptyline, a drug that baclofen can be slowly increased from 5 mg to 80 relieves the shocklike pains of PHN, is not effec- mg per day, depending on the response and side effects. Often the drug needs to be taken every 4hours because of its short half-life. Baclofen doesnot have carbamazepine’s potential for life-threat- ening side effects; it most commonly causesdrowsiness, dizziness, and gastrointestinal reac- There is little scientific evidence in the form of tions. About 10% of patients cease treatment on RCTs of therapeutic approaches for this group monotherapy because of side effects. One should other than in PHN. Sharav et al27 found that never stop baclofen suddenly, since hallucinations amitriptyline was effective in an RCT of chronic facial pain but thought most subjects had evidence Phenytoin may also be used as monotherapy, but it is much less effective than carbamazepine, COPYRIGHT 2004 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
Shocklike pain, steady pain (allodynia), skin sensitivity (hyperesthe-sia, dysesthesia) Damage to dorsal horn,nerve root, nerve, and spinal cord Relief in 80% of patients with Some relief in up to(1) Decompression of because of side effects and the fact that relief israrely complete and occurs in only about two thirds Antidepressants. A large number of studies sup- port the utility of antidepressants in a variety of One of the effects of this drug is to potentiate chronic pain problems. An important part of this both serotonin and noradrenaline in the central ner- literature concerns favorable, well-designed trials vous system. Subsequent studies have explored of the use of these agents in neuropathic pain, par- whether selective serotonergic or noradrenergic ticularly PHN.28–32 PHN is a good model of neuro- antidepressants might be more effective and have pathic pain for drug trials because, if patients are fewer untoward effects.30–32 Experience with sero- chosen carefully, the pain is fairly stable over time tonergic agents (clomipramine, trazodone, nefa- and sufficient numbers of cases for trials can be zodone, fluoxetine, and zimelidine) in PHN has been readily obtained. Most studies include trigeminal disappointing.33 The evidence supporting the use of PHN (about 20% of PHN cases are trigeminal noradrenergic agents is more compelling.
PHN). Antidepressant therapy, as opposed to Desipramine, a selective norepinephrine reuptake many other putative therapies of this difficult inhibitor, has been shown to be more effective than problem, has come to have a sound scientific basis.
placebo in PHN,30 and pain relief with this drug was The earliest RCT of amitriptyline as a placebo found not to be mediated by mood elevation. An control found good results in 16 of 22 patients RCT comparing maprotiline (a noradrenergic agent) (67%).28 Most patients were not depressed, and with amitriptyline found that both were effective; pain relief occurred without a change in depression amitriptyline was the more effective of the 2.31 Nine ratings in most patients, indicating that the drug patients responded equally well to both drugs, 7 appeared to result in pain relief independently of its responded only to maprotiline and 8 required antidepressant effect. This analgesia occurred at amitriptyline for good relief. All 3 aspects of PHN lower doses than those usually used to treat depres- pain (ie, steady pain, brief jabbing pain, and pain on sion (median 75 mg). Median follow-up was 12 tactile skin contact) responded to treatment in this months. Two patients were lost to follow-up; a study. Side effects were troublesome with both good result was maintained in 12 of 22 (55%). A agents, limiting their effectiveness. Most patients subsequent trial has corroborated these results.29 were not depressed, and pain relief occurred in most Amitriptyline has limitations in the long term without a change in depression rating scales. A com- COPYRIGHT 2004 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
parison of amitriptyline with nortriptyline (which is older generation antidepressant or gabapentin (Fig more noradrenergic than amitriptyline) showed 1). These data indicate that pain may be reduced about equal efficacy for both drugs, with less severe from moderate or severe to mild in about 50% to 60% of patients by commencing with amitriptyline or nortriptyline at a dose of 10 mg qhs in those gabapentin in PHN.9,34 These studies found 20% to over 65 years old and 25 mg in those younger than 30% of patients to have at least moderate improve- 65. The dose is increased by similar increments in a ment (ie, 50% improvement) over placebo with single hs dose every 7 to 10 days until relief is few serious side effects. Many patients in 1 study obtained or intolerable side effects interfere with achieved the target dose of 3,600 mg per day.
the treatment. If these agents fail, desipramine or Opioids. For a long time, there has been a bias maprotiline can be tried in similar doses.
against the use of opioids for noncancer pain.
Occasional patients failing these may benefit from a There is now increasing support for the view that serotonergic drug such as trazodone, clomipramine, these drugs are helpful and justifiable for use with or fluoxetine, but these do not appear useful for the noncancer pain, including neuropathic pain.
majority of patients. Gabapentin has a modest Survey data in PHN have indicated that opioids effect with few severe side effects; divided doses up are useful for some patients.33 Twenty-five of 90 to 3,600 mg may be required. A trial-and-error patients with otherwise intractable pain achieved approach in refractory patients may also include good to excellent results, and 50 others had 25% the anticonvulsants carbamazepine, phenytoin, to 50% relief. In an RCT11 of 50 patients treated clonazepam and valproic acid. For resistant cases, with sustained release oxycodone, 58% of patients opioids may be safely prescribed on an as-needed had at least moderate improvement versus 18% or round-the-clock basis. Long-acting oral forms of oxycodone, morphine, and hydromorphone and Topical Agents. A variety of topical agents (cap- the fentanyl skin patch may be helpful. Trials of saicin, acetylsalicylic acid, and local anesthetics) different opioids may reveal one that is preferred.
have been studied in PHN.35 Capsaicin, the active The use of topical agents, such as capsaicin, ingredient in red peppers and other plants, acts by acetylsalicylic acid, and local anesthetic agents is depleting the neurotransmitter substance P in small attractive as it is simple and free of systemic primary afferent fibers. Capsaicin has a modest effects. The most useful of these appears to be the effect according to RCTs and may best be used as lidocaine patch, but this may be difficult or impos- an adjunct to other treatments.35 The burning sen- sible to use, as it may be considered cosmetically sation induced by capsaicin is often unpleasant or unacceptable on the head and face. For most unbearable and limits therapy. A recent RCT of patients, topical agents do not appear useful as the lidocaine patch (Lidoderm) has indicated effi- sole therapy, but they may be a useful adjunct to cacy in PHN.36 The patch itself has been found to other therapies in some individuals.
offer protection, but a significant drug effect was Transcutaneous electrical nerve stimulation, also present with this simple topical approach.
although unproven by RCT, may be worth trying.
NNT data for different drugs used for the neuro- Electrode placement, frequency, intensity, and pathic pain disorders of PHN, painful diabetic neu- duration of stimulation are a matter of trial and ropathy, and other neuropathies are given in Table error. There are no good favorable data for 1. These data should be interpreted with caution acupuncture in PHN. Some patients may benefit because they compare different trial designs, num- from nerve blocks which, if efficacious, may be bers of patients, and data analyses. Unfortunately, repeated at appropriate intervals. These have not few head-to-head trials exist that allow direct com- parisons of analgesic drugs of differing classes.
In at least 40% of patients, pain remains totally Also, because of patient selection in RCTs, NNT refractory or unsatisfactorily relieved. These data may not be generalizable to clinical practice.
patients should be seen regularly. Different opioids,along with any approaches that seem reasonable Suggested Treatment of PHN and Neuropathic and safe, should be tried for the limited relief they give, with the hope that improvement will occurwith time. Approximately 50% of patients, even In conclusion, a reasonable first-line approach for those with pain of long duration, will improve over facial neuropathic pain other than TN is either an the years, half of these with no treatment.37 COPYRIGHT 2004 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
similar to the therapy of TN may be best, with car- bamazepine as the first approach (althoughamitriptyline and nortriptyline also relieve shock- The clinical features and pharmacologic treatment like pain). Chronic opioid therapy may be neces- of TN and PHN are very different (Table 3).
sary to provide at least some relief if the pain is Amitriptyline or nortriptyline and gabapentin are constant, severe, and intractable to all other mea- the first-line drugs for PHN, while carbamazepine sures. Generally it is wise to avoid ablative neuro- is the first-line drug for TN. At least 80% of TN surgical procedures for neuropathic facial pain patients find relief with carbamazepine, whereas opioids and amitriptyline have been found to haveno effect on TN. About 50% to 60% of PHNpatients respond to amitriptyline, nortriptyline, gabapentin, or opioids. These pharmacologic dif-ferences suggest different pathophysiological Trigeminal neuralgia and PHN may occupy oppo- site ends of the spectrum of neuropathic facial painand these disorders may depend upon the differentlocation and severity of the insult to the nerve.
Probably both disorders result in reduced inhibi-tion and excess excitation of hyperactive, damaged Many other conditions may cause trigeminal neu- central neurons in the nucleus of the trigeminal ropathy, with and without pain in the nerve and nerve. Clinical and pharmacological differences nerve root.38,39 A large group of conditions are dif- point to different pain mechanisms and require ficult to categorize as to cause and have been further elucidation. First-line therapy for TN is grouped together as atypical facial pain. In the carbamazepine whereas amitriptyline, nortripty- author’s view, a substantial proportion of these are line, and gabapentin are first choices for PHN and neuropathic because they occur after situations other neuropathic facial pain. In refractory cases which can cause nerve injury such as root canal opioids are reasonable but they do not relieve TN.
therapy and dental extractions. Trauma to facial The drug therapy of PHN may be extrapolated to structures and the skull may damage branches of other neuropathic trigeminal pain conditions.
the fifth nerve such as the supraorbital and There continues to be a need for RCTs of new infraorbital nerves. Mental nerve neuropathy may drugs in TN and especially in neuropathic facial be the first sign of cancer. Neurotoxins such as trichloroethylene and stilbamidine are known toaffect the fifth nerve. Inflammatory conditions ofthe ear and petrous apex may spread to the nerve root or ganglion and also involve the sixth nerve.
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